Dataset Information

Genome-wide association study reveals novel genetic loci: a new polygenic risk score for mitral valve prolapse.

ABSTRACT:

Aims

Mitral valve prolapse (MVP) is a common valvular heart disease with a prevalence of >2% in the general adult population. Despite this high incidence, there is a limited understanding of the molecular mechanism of this disease, and no medical therapy is available for this disease. We aimed to elucidate the genetic basis of MVP in order to better understand this complex disorder.

Methods and results

We performed a meta-analysis of six genome-wide association studies that included 4884 cases and 434 649 controls. We identified 14 loci associated with MVP in our primary analysis and 2 additional loci associated with a subset of the samples that additionally underwent mitral valve surgery. Integration of epigenetic, transcriptional, and proteomic data identified candidate MVP genes including LMCD1, SPTBN1, LTBP2, TGFB2, NMB, and ALPK3. We created a polygenic risk score (PRS) for MVP and showed an improved MVP risk prediction beyond age, sex, and clinical risk factors.

Conclusion

We identified 14 genetic loci that are associated with MVP. Multiple analyses identified candidate genes including two transforming growth factor-β signalling molecules and spectrin β. We present the first PRS for MVP that could eventually aid risk stratification of patients for MVP screening in a clinical setting. These findings advance our understanding of this common valvular heart disease and may reveal novel therapeutic targets for intervention.

SUBMITTER: Roselli C

PROVIDER: S-EPMC9649914 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Publications

Genome-wide association study reveals novel genetic loci: a new polygenic risk score for mitral valve prolapse.

Roselli Carolina C Yu Mengyao M Nauffal Victor V Georges Adrien A Yang Qiong Q Love Katie K Weng Lu-Chen LC Delling Francesca N FN Maurya Svetlana R SR Schrölkamp Maren M Tfelt-Hansen Jacob J Hagège Albert A Jeunemaitre Xavier X Debette Stéphanie S Amouyel Philippe P Guan Wyliena W Muehlschlegel Jochen D JD Body Simon C SC Shah Svati S Samad Zainab Z Kyryachenko Sergiy S Haynes Carol C Rienstra Michiel M Le Tourneau Thierry T Probst Vincent V Roussel Ronan R Wijdh-Den Hamer Inez J IJ Siland Joylene E JE Knowlton Kirk U KU Jacques Schott Jean J Levine Robert A RA Benjamin Emelia J EJ Vasan Ramachandran S RS Horne Benjamin D BD Muhlestein Joseph B JB Benfari Giovanni G Enriquez-Sarano Maurice M Natale Andrea A Mohanty Sanghamitra S Trivedi Chintan C Shoemaker Moore B MB Yoneda Zachary T ZT Wells Quinn S QS Baker Michael T MT Farber-Eger Eric E Michelena Hector I HI Lundby Alicia A Norris Russell A RA Slaugenhaupt Susan A SA Dina Christian C Lubitz Steven A SA Bouatia-Naji Nabila N Ellinor Patrick T PT Milan David J DJ

European heart journal 20220501 17

<h4>Aims</h4>Mitral valve prolapse (MVP) is a common valvular heart disease with a prevalence of >2% in the general adult population. Despite this high incidence, there is a limited understanding of the molecular mechanism of this disease, and no medical therapy is available for this disease. We aimed to elucidate the genetic basis of MVP in order to better understand this complex disorder.<h4>Methods and results</h4>We performed a meta-analysis of six genome-wide association studies that includ ...[more]

PMID: 35245370

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Project description:BackgroundInitial studies have suggested the familial clustering of mitral valve prolapse, but most of them were either community based among unselected individuals or applied non-specific diagnostic criteria. Therefore little is known about the familial distribution of mitral regurgitation in a referral-type population with a more severe mitral valve prolapse phenotype. The objective of this study was to evaluate the presence of familial mitral regurgitation in patients undergoing surgery for mitral valve prolapse, differentiating patients with Barlow's disease, Barlow forme fruste and fibro-elastic deficiency.MethodsA total of 385 patients (62 ± 12 years, 63% men) who underwent surgery for mitral valve prolapse were contacted to assess cardiac family history systematically. Only the documented presence of mitral regurgitation was considered to define 'familial mitral regurgitation'. In the probands, the aetiology of mitral valve prolapse was defined by surgical observations.ResultsA total of 107 (28%) probands were classified as having Barlow's disease, 85 (22%) as Barlow forme fruste and 193 (50%) patients as fibro-elastic deficiency. In total, 51 patients (13%) reported a clear family history for mitral regurgitation; these patients were significantly younger, more often diagnosed with Barlow's disease and also reported more sudden death in their family as compared with 'sporadic mitral regurgitation'. In particular, 'familial mitral regurgitation' was reported in 28 patients with Barlow's disease (26%), 15 patients (8%) with fibro-elastic deficiency and eight (9%) with Barlow forme fruste (P < 0.001).ConclusionsIn a large cohort of patients operated for mitral valve prolapse, the self-reported prevalence of familial mitral regurgitation was 26% in patients with Barlow's disease and still 8% in patients with fibro-elastic deficiency, highlighting the importance of familial anamnesis and echocardiographic screening in all mitral valve prolapse patients.

Project description:Background Mitral valve prolapse (MVP) is one of the most common forms of cardiac valve disease and affects 2% to 3% of the population. Previous imaging reports have indicated that myocardial fibrosis is common in MVP and described its association with sudden cardiac death. These data combined with evidence for postrepair ventricular dysfunction in surgical patients with MVP support a link between fibrosis and MVP. Methods and Results We performed histopathologic analysis of left ventricular (LV) biopsies from peripapillary regions, inferobasal LV wall and apex on surgical patients with MVP, as well as in a mouse model of human MVP (Dzip1S14R/+). Tension-dependent molecular pathways were subsequently assessed using both computational modeling and cyclical stretch of primary human cardiac fibroblasts in vitro. Histopathology of LV biopsies revealed regionalized fibrosis in the peripapillary myocardium that correlated with increased macrophages and myofibroblasts. The MVP mouse model exhibited similar regional increases in collagen deposition that progress over time. As observed in the patient biopsies, increased macrophages and myofibroblasts were observed in fibrotic areas within the murine heart. Computational modeling revealed tension-dependent profibrotic cellular and molecular responses consistent with fibrosis locations related to valve-induced stress. These simulations also identified mechanosensing primary cilia as involved in profibrotic pathways, which was validated in vitro and in human biopsies. Finally, in vitro stretching of primary human cardiac fibroblasts showed that stretch directly activates profibrotic pathways and increases extracellular matrix protein production. Conclusions The presence of prominent regional LV fibrosis in patients and mice with MVP supports a relationship between MVP and progressive damaging effects on LV structure before overt alterations in cardiac function. The regionalized molecular and cellular changes suggest a reactive response of the papillary and inferobasal myocardium to increased chordal tension from a prolapsing valve. These studies raise the question whether surgical intervention on patients with MVP should occur earlier than indicated by current guidelines to prevent advanced LV fibrosis and potentially reduce residual risk of LV dysfunction and sudden cardiac death.

Dataset Information

Genome-wide association study reveals novel genetic loci: a new polygenic risk score for mitral valve prolapse.

Aims

Methods and results

Conclusion

Publications

Genome-wide association study reveals novel genetic loci: a new polygenic risk score for mitral valve prolapse.

Similar Datasets

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